Nuclear genome instability, a hallmark of cancer, is thought to be an early event in tumorigenesis including malignancies induced from IR either from incidental exposure or secondary to therapy. It is well established that mammalian cells contain fidelity proteins that appear to protect against both endogenous and exogenous forms of genotoxic stress including ionizing radiation (IR)-induced genomic instability. This idea is based on one of the fundamental paradigms in biology: that is mammalian cells contain fidelity proteins that recognize specific conditions, including cell damage, and subsequently initiate signaling cascades that maintain cellular homeostatic poise. In addition, loss of function or genetic mutation of these fidelity proteins has been shown to create tumor permissive cellular phenotype suggesting that these proteins also function as tumors suppressors (TS). Preliminary data in our laboratory suggests that SIRT3, which is a genomically expressed, mitochondrial localized protein, is TS and cells lacking SIRT3 exhibit increased IR- induced genomic instability. Thus, the overarching goal of this proposal is to determine a mechanistic connection between SIRT3, mitochondrial metabolism, specifically superoxide levels, and IR genomic instability as well as IR-induced cancers. In this proposal we hypothesize that SIRT3 protects against IR-induced genomic instability and carcinogenesis via the regulation of MnSOD activity and the post translation modification of a reversible acetyl lysine. In addition, we are also proposing that lysine acetylation may be a primary posttranslational modification employed to regulate mitochondrial proteins. To investigate a mechanistic connection between SIRT3, MnSOD, and IR-induced genomic instability a series of in vitro and in vivo model systems will be used. PUBLIC HEALTH RELEVANCE: Nuclear genome instability, a hallmark of cancer, is thought to be an early event in tumorigenesis including malignancies induced from IR either from incidental exposure or secondary to therapy. In this proposal we suggest that the mitochondrial is an important target in IR-induced genomic instability and carcinogenesis.